The behavioral and biochemical effects of GABAergic drugs on the septal-hippocampal system was studied by comparing the acetylcholine turnover rate (TRACh) in the rat hippocampus with extinction of a food reinforced lever press response after intraseptal injection of such drugs. Muscimol, a GABAAlpha agonist, produced a dose dependent and simultaneous increase in responding during extinction and decrease in TRACh. Bicuculline, a GABAAlpha antagonist, in equivalent doses, had the opposite behavioral effect, i.e. a general decrease in responding. Baclofen, a GABABeta agonist, had behavioral effects similar to those produced by muscimol, but was 5-10 times more potent and did not alter the hippocampal TRACh. Three to five weeks after bilateral injection of kainic acid into the hippocampus, there was a significant loss of bicuculline-insensitive GABA binding (GABABeta sites) in the septum, but no loss of baclofen insensitive GABA binding (GABAAlpha sites). This loss is presumably due to the degeneration of the glutamatergic hippocampal pyramidal cells which have terminals in the lateral septum. We hypothesize that both muscimol and baclofen exert their behavioral effects by decreasing the functional output of the hippocampus, muscimol by decreasing the stimulatory input to the hippocampus, and baclofen by presynaptically inhibiting the hippocampal efferents to the septum.